PROJECT SUMMARY Diabetic retinopathy (DR) is a complication of diabetes and a leading cause of blindness in the world. Although it is widely accepted that DR is driven by ischemia, the current grading of DR severity is based only on structural alterations such as the presence of abnormal retinal microvasculature in non-proliferative DR or angiogenesis in proliferative DR. As a result, most patients have already developed irreversible retinal functional impairment when they first receive their DR diagnosis. DR develops through progressively increasing capillary non-perfusion leading to insufficient blood supply to meet the metabolic demand of the inner retinal neurons. This causes retinal ischemia, which activates signaling pathways that promote angiogenesis and herald the proliferative phase of retinopathy. If not managed in a timely fashion, proliferative DR can ultimately lead to blindness. Therefore, non-invasive imaging of retinal metabolic rate of oxygen is expected to improve our understanding of DR pathophysiology as well as significantly enhance our ability to diagnose and manage high-risk DR. This proposal aims to maximize the likelihood of translation and integration of a novel visible-light optical coherence tomography or vis-OCT into clinical management of DR. We seek to design, develop, and optimize the first clinical-prototype vis-OCT instrument to quantify retinal metabolic rate of oxygen in normal human subjects as well as in patients with diabetes. We believe that the proposed technology has the potential to transform the existing clinical practice of DR from anatomy-based approach to a more sensitive and objective function-based approach. The proposed work is built on Opticent Health?s successful meeting the goals in the Phase I project and on close collaboration with leading clinician-scientists.